Uric Acid

Biochemistry and Physiology of Uric Acid: Production.- 1 Uric Acid: Chemistry and Synthesis.- A. Introduction.- B. Structure.- C. Properties.- D. Synthesis.- I. Synthesis from Imidazoles.- II. One-Pot Synthesis.- E. Biosynthesis of Purines.- F. Uricotelism.- G. Uricolysis.- H. Measurement of Uric Acid Synthesis in Man.- J. Uric Acid Formation from Purines.- References.- 2 Regulation of Biosynthesis De Novo.- A. Introduction.- B. Rate-Limiting Step.- C. Enzymatic Activities Leading to PRA Synthesis.- D. Properties of Human PP-ribose-P Amidotransferase.- E. Studies with Intact Cells.- F. Studies In Vivo.- G. Conclusion.- References.- 3 Purine Salvage Enzymes.- A. Introduction.- B. Normal Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT).- I. Assay Methods and Kinetic Properties.- II. Physical Properties.- III. Role in Cellular Transport of Purines.- C. Clinical Syndromes Associated with a Deficiency of HGPRT.- I. Lesch-Nyhan Syndrome.- 1. Characteristics of the Mutant HGPRT in Patients with the Lesch-Nyhan Syndrome.- 2. Inheritance of HGPRT.- 3. Pathogenesis of the Neurobehavioral Disorder.- 4. Secondary Metabolic and Enzymatic Abnormalities.- II. Partial Deficiency of HGPRT.- 1. Characteristics of the Mutant HGPRT Enzyme in Patients with a Partial Deficiency of HGPRT Activity.- 2. Inheritance of Partial HGPRT Deficiency.- 3. Secondary Metabolic and Enzymatic Abnormalities.- D. Normal Adenine Phosphoribosyltransferase (APRT).- I. Assay Methods and Kinetic Properties.- II. Physical Properties.- III. Role in Cellular Transport of Purines.- E. Clinical Syndromes Associated with a Deficiency of APRT.- I. Partial Deficiency of APRT.- 1. Characteristics of the APRT Enzyme in Patients with a Partial Deficiency.- 2. Metabolic Abnormalities Associated with a Partial APRT Deficiency.- II. Complete Deficiency of APRT Activity.- References.- 4 Purine Nucleotide Interconversions.- A. Pathways of Purine Nucleotide Interconversion.- B. Regulation of Enzymes of Purine Nucleotide Interconversion in Intact Mammalian Cells.- I. Enzyme Amount and Localization.- II. Substrate Concentrations.- III. Alternative Pathways of Substrate Metabolism.- IV. Effects of Other Metabolites.- C. Functions of the Reactions of Purine Nucleotide Interconversion in Mammalian Cells.- I. Biosynthesis of ATP and GTP.- II. Balance Between ATP and GTP Concentrations.- III. Catabolism of Adenine and Guanine Nucleotides.- IV. Deamination of Amino Acids.- D. Effects of Drugs on the Reactions of Purine Nucleotide Interconversion.- References.- 5 Degradation of Purine Nucleotides.- A. Introduction.- B. Reactions of Purine Nucleotide Degradation.- C. Properties of Purine Catabolic Enzymes.- I. 5?-Nucleotidase(E.C.3.1.3.5) and Other Phosphatases.- II. Purine Nucleoside Phosphorylase (E.C.2.4.4.1.- III. Adenosine Deaminase (E.C.3.5.4.6).- IV. Guanine Deaminase (E.C.3.5.4.3).- V. Xanthine Oxidase (E.C.1.2.3.2).- D. Regulation of Purine Nucleotide Degradation.- E. Inborn Errors of Purine Nucleotide Degradation.- I. Adenosine Deaminase Deficiency.- II. Purine Nucleoside Phosphorylase Deficiency.- III. Xanthinuria.- IV. Other Disorders.- F. Relationship of Purine Nucleotide Degradation to Immune Function.- G. Other Relationships to Purine Nucleotide Degradation.- H. Conclusions.- References.- 6 Interrelationship of Purine and Pyrimidine Metabolism.- A. Introduction.- B. Control of Enzyme Activity by Pyrimidines in Purine Biosynthetic Pathways.- I. Phosphoribosyl Pyrophosphate Amidotransferase.- II. Adenylosuccinate Synthetase.- III. IMP Dehydrogenase.- IV. Adenosine Kinase.- C. Control of Enzyme Activity by Purines in Pyrimidine Biosynthetic Pathways.- I. Carbamoyl-Phosphate Synthetase II.- II. Aspartate Carbamoyltransferase.- III. Orotate Phosphoribosyltransferase.- IV. Orotidylate Decarboxylase.- V. Cytidine Triphosphate Synthetase.- VI. Uridine-Cytidine Kinase.- D. Regulation of the Ribonucleotide System.- E. Disorders in Nucleotide Biosynthesis Induced by Exogenous Purines and Pyrimidines.- I. Disorders in Purine Biosynthesis Induced by Orotate.- II. Inhibition of Pyrimidine Nucleotide Synthesis by Adenine.- III. Interference of Adenosine and Other Purine Nucleosides with Pyrimidine Biosynthesis.- IV. Effects of Allopurinol on Pyrimidine Biosynthesis De Novo.- F. Role of Cellular Levels of Phosphoribosyl Pyrophosphate in Coordinate Control of Purine and Pyrimidine Nucleotide Biosynthesis.- G. Possible Interrelationship Between Catabolism of Purine and Pyrimidine Nucleotides.- I. Dephosphorylation of Purine and Pyrimidine Mononucleotides.- II. Cleavage of Glycosidic Bond.- H. Possible Interference Between Purine and Pyrimidine Transport.- I. Conclusion.- References.- 7 Abnormalities of PRPP Metabolism Leading to an Overproduction of Uric Acid.- A. Introduction.- B. Metabolism of PRPP.- I. Utilization of PRPP.- II. Intracellular PRPP Concentration.- III. Determinants of PRPP Synthesis.- 1. PRPP Synthetase.- 2. Substrates.- 3. Inhibitors.- 4. Activators.- 5. Structure and Activity of PRPP Synthetase.- 6. Control of the Amount of PRPP Synthetase.- C. PRPP Availability and the Rate of Purine Synthesis De Novo.- I. Studies of Amidophosphoribosyltransferase and Its Effectors.- II. Effects of Pharmacologic Agents on PRPP Concentration and Purine Synthetic Rate.- D. Studies of PRPP Metabolism in Uric Acid Overproducers Without Recognized Enzyme Defects.- E. PRPP Metabolism in Enzyme Defects Associated with Uric Acid Overproduction.- I. Increased PRPP Production.- 1. Excessive PRPP Synthetase Activity.- 2. Glucose-6-phosphatase Deficiency.- 3. Increased Glutathione Reductase Activity.- II. Decreased PRPP Use.- 1. HGPRT Deficiency.- 2. APRT Deficiency.- 3. Purine Nucleoside Phosphorylase Deficiency.- References.- Biochemistry and Physiology of Uric Acid: Renal Disposal.- 8 Urate Excretion in Nonmammalian Vertebrates.- A. Introduction.- B. Occurrence of Urates as the Primary Excretory Products of Nitrogen Metabolism.- C. The Process of Renal Excretion of Urates.- I. Filtration at the Glomerulus.- II. Transport by the Renal Tubules.- 1. Direction of Net Urate Transport.- 2. Sites of Tubular Transport.- 3. Process of Tubular Transport.- 4. Specificity of Tubular Transport.- D. Chemical Forms of Urates in Urine.- I. Forms in Liquid Phase of Urine.- II. Forms in Urine Precipitates.- III. Modification of Form and Ionic Content of Urates by Transport Processes in Bladder or Cloaca.- E. Concluding Remarks.- References.- 9 Urinary Excretion of Uric Acid in Nonhuman Mammalian Species.- A. Introduction.- B. Methods of Investigation.- I. Clearance Methods.- II. Stop-flow Analysis.- III. The Double-Isotope-Precession Method.- IV. Micropuncture Methods.- 1. Microinjection Technique.- 2. Microperfusion of Tubular Segments In Vivo.- 3. Microperfusion of Isolated Tubular Segments from Rabbits In Vitro.- 4. Free-flow Micropuncture.- 5. Uptake of Uric Acid by Renal Tissue.- V. Analytic Methods Used for Measuring Urate Concentrations in Body Fluids.- VI. Overall Renal Function and Plasma Concentrations of Uric Acid in Various Mammalian Species.- C. Rabbit.- I. Ultrafilterability of Urate.- II. Fractional Excretion of Urate.- III. Micropuncture Studies and Microperfusion of Isolated Tubular Segments.- IV. Uptake of Urate into Renal Cortical Tissue In Vitro.- V. Drug Effects.- VI. Conclusion.- D. Dog.- I. Comparison of Dalmatian and Non-Dalmatian Dogs.- II. Effects of Drugs.- III. Conclusion.- E. Rat.- I. Plasma Concentration and Ultrafilterability of Urate.- II. Fractional Excretion of Urate.- III. Site and Nature of Transtubular Movements of Urate.- 1. Proximal Convoluted Tubules.- 2. Henle’s Loops.- 3. Distal Convoluted Tubules.- 4. Collecting Ducts.- IV. Effects of Drugs.- V. Experimental Hyperuricemia.- VI. Conclusion.- F. Mouse.- G. Guinea Pig.- H. Pig.- J. Nonhuman Primates.- I. Old-World Monkeys.- II. New-World Monkeys.- 1. Effects of Drugs and Metabolites.- III. Apes.- IV. Conclusion.- K. Isolated Data on Other Species of Mammals.- L. Conclusions.- References.- 10 Urate Excretion in Man, Normal and Gouty.- A. Introduction.- B. Development of Concepts of Renal Urate Handling.- C. Factors Thought to Affect Urate Excretion in Normal Man.- I. Sequence of Renal Reabsorptive and Secretory Transport Sites.- II Plasma Urate and GFR.- III. Urate Binding by Plasma Proteins.- IV. Extracellular Fluid Volume and the Renal Circulation.- V. Urine Flow.- VI. Urine pH.- VII. Angiotensin and Other Vasoactive Substances.- VIII. Relation of Urate Transport to Other Organic Compounds.- IX. Possibility of Intrarehal Urate Synthesis.- X. Red Cell Uptake and Renomedullary Accumulation.- D. Urate Excretion in Gout.- I. Classification of Gout.- II. Chronic Renal Disease with Gout.- E. Conclusion.- References.- 11 Abnormal Urate Excretion Associated with Renal and Systematic Disorders, Drugs, and Toxins.- A. Introduction.- B. Renal Response to Increased Urate Production.- I. Over-Excretion with Over-Production of Urate.- II. Over-Excretion of Uric Acid Due to Dietary Variables, Especially Purine Consumption.- III. Over-Production with Under-Excretion of Urate.- C. Renal Causes of Abnormal Urate Metabolism.- I. Abnormal Renal Excretion of Urate not Associated with Chronic Disease.- 1. Genetic Tubular Dysfunction.- a) Urate-Losing Disorders.- b) Urate-Retaining Disorders.- 2. Reversible Tubular Dysfunction.- a) Metabolites.- b) Drugs.- c) Toxins.- II. Abnormal Renal Excretion of Urate Associated with Chronic Renal Disease.- D. Drugs Affecting Urate Excretion.- I. Drugs that have a Biphasic Action on Renal Excretion of Urate.- 1. Uricosuric Drugs.- 2. Aspirin.- 3. Diuretics.- 4. Pyrazinamide.- II. Drugs that Increase Renal Excretion of Urate.- III. Drugs that Reduce the Renal Excretion of Urate.- IV. Drugs that Alter Urate Excretion by Altering Urate Production.- 1. Drugs that Increase Urate Production.- 2. Drugs that Reduce Purine Production.- E. Systemic Conditions Leading to Abnormal Urate Metabolism.- I. Hypertension.- II. Obesity.- III. Regular Alcohol Consumption.- IV. Hyperlipidemia.- V. Degenerative Vascular Disease.- VI. Acute Myocardial Infarction.- VII. Diabetes.- VIII. Myxedema.- IX. Parathyroid Disease.- X. Glycogen Storage Disease.- XI. Fructose Administration.- XII. Toxemia of Pregnancy.- XIII. Liver Disease.- XIV. Sarcoidosis and Chronic Beryllium Disease.- XV. Respiratory Acidosis.- XVI. Psoriasis.- XVII. Infectious Mononucleosis.- XVIII. Estrogen Therapy.- XIX. Down’s Syndrome.- XX. Hodgkin’s Disease and Other Malignancies.- References.- Biochemistry and Physiology of Uric Acid: Extrarenal Disposal.- 12 Extrarenal Disposal of Uric Acid.- A. Introduction.- B. The Uricolytic Enzyme System.- C. Recovery of Injected Isotopic Uric Acid.- I. Recovery of Isotopic Uric Acid in Urine.- II. Recovery of Isotopic Uric Acid in Degradation Products.- D. Site of Uricolysis.- E. Extrarenal Excretion of Uric Acid.- F. Conclusion.- References.- Pathology of Uric Acid: Acute Gouty Arthritis.- 13 Initial Events in the Development of an Acute Attack of Gouty Arthritis.- A. Introduction.- B. How Do Crystals Appear in the Joint?.- I. Precipitation in Synovial Fluid.- II. Deposition in Synovial Membrane.- C. How Do Urate Crystals Induce Inflammation in the Joint?.- I. Why Do Crystals not Always Seem to Produce Inflammation?.- II. How Can Crystals Induce Inflammation After Arrival in the Joint Fluid ?.- 1. Intra-Articular Injection of Urates.- 2. In Vitro Studies of Crystal-Cell Interaction.- 3. Immunologic Contributions.- D. Conclusion.- References.- 14 Role of Proteoglycans in the Development of Gouty Arthritis.- A. Introduction.- B. Historical Background.- C. The Deposition Phenomenon: Modern Connective Tissue Concepts.- I. Solubility of Monosodium Urate in Bovine Tissues.- II. Detection of a Urate-Solubilizing Substance in Connective Tissue.- III. Solubility of Monosodium Urate in Polysaccharide Solutions.- IV. Inhibition of Urate Crystallization by Polysaccharides.- V. Induction of Urate Crystallization from Polysaccharide Solutions Saturated with Urate.- VI. Induction of Urate Crystallization from Human Synovial Fluid.- D. Speculations on Altered Connective Tissue Metabolism in Gout.- I. Normal Connective Tissue Metabolism.- II. Accelerated Connective Tissue Metabolism as a Cause of Urate Deposition.- E. Effect of Colchicine on Connective Tissue Metabolism.- F. Diagnostic Value of Serum Glycosaminoglycans Determination.- G. Conclusion.- References.- 15 Role of the Leukocyte and Chemical Mediators of the Acute Gouty Attack.- A. Phagocytosis of Crystals.- B. Mediators of the Inflammatory Response.- C. Termination of the Acute Gouty Attack.- References.- 16 Role of Local Factors in the Precipitation of Urate Crystals.- A. Introduction.- B. Temperature.- C. pH.- D. Cavitation.- E. Osteoarthritis.- F. Concentration.- G. Shoes.- H. Crystal Deposits.- J. Conclusion.- References.- Pathology of Uric Acid: Nephrolithiasis and Urate Nephropathy.- 17 Uric Acid Nephrolithiasis.- A. Introduction.- B. Prevalence of Uric Acid Nephrolithiasis.- C. Chemistry of Uric Acid.- D. Structure and Formation of Uric Acid Stones.- E. Association of Other Crystalline Constituents in Uric Acid Stones.- F. Pathogenesis of Uric Acid Nephrolithiasis.- I. Hyperuricosuria and Hyperuricemia.- II. Undue Urinary Acidity and Subnormal Ammonium Excretion.- III. Organic Matrix and Crystallization.- G. Natural History of Uric Acid Nephrolithiasis.- I. Primary Gout and Hyperuricemia Without Gout.- II. Uric Acid Lithiasis in Secondary Gout, Associated with Blood Dyscrasia.- III. Hypoxanthine Guanine Phosphoribosyl Transferase (HPRT) Deficiency and Other Enzyme Abnormalities.- IV. Chronic Renal Disease.- V. Chronic Ulcerative Colitis and Regional Ileitis.- VI. Idiopathic Uric Acid Lithiasis.- H. Detection of the Chemical Nature of the Stone.- J. Management of Uric Acid Nephrolithiasis.- I. Correction of Undue Urine Acidity.- 1. Adequate Hydration.- 2. Sensible Diet.- 3. Alkalinizing Agents.- II. Control of Infection.- III. Control of Hyperuricosuria—Allopurinol.- K. Conclusion.- References.- 18 Association of Calcium Nephrolithiasis with Disorders of Uric Acid Metabolism.- A. Introduction.- B. Frequency of Hyperuricosuria in Calcium Stone Formers.- C. Mechanisms of Hyperuricosuria.- I. Role of Diet.- II. Role of Over-Production.- III. Possible Renal Tubular Disturbance.- D. Natural History of Stone Disease.- E. Urate-Oxalate Epitaxis.- I. Crystallographic Evidence.- II. Heterogeneous Nucleation.- F. Reduced Urine Inhibitors.- G. Allopurinol Treatment.- H. Conclusion.- References.- 19 Pathology of Urate Nephropathy.- A. Introduction.- B. Gross Examination.- C. Acute Obstructive Uric Acid Nephropathy in Blood Dyscrasias and Neoplasms.- D. Experimental Production of Acute Uric Acid Nephropathy.- E. Structural Alterations in the Gouty Kidney.- F. Miscellaneous Observations.- G. Selected Laboratory Procedures.- I. Roentgenography.- II. Renal Biopsy.- H. Conclusion.- References.- Pharmacology of Uric Acid.- 20 Uricosuric Drugs.- A. Introduction.- B. Tubular Transport of Uricosuric Drugs.- C. Drug Metabolism.- D. Mechanisms of Uricosuria.- E. Clinical Pharmacology and Use.- F. Clinically Important Uricosuric Drugs.- I. Probenecid.- 1. Chemistry, Methods of Assay, and Pharmacokinetics.- 2. Biologic Effects.- 3. Toxicology.- II. Sulfinpyrazone and Related Pyrazolidinediones.- 1. Method of Assay.- 2. Pharmacokinetics.- 3. Biologic Effects.- 4. Toxicology.- III. Benzbromarone and Related Drugs.- 1. Pharmacokinetics and Assay.- 2. Biologic Effects.- 3. Toxicology.- IV. Tienilic Acid (Ticrynafen) and Other Uricosuric Diuretics.- 1. Pharmacokinetics and Assays.- 2. Biologic Effects.- 3. Toxicology.- References.- 21 Allopurinol and Other Inhibitors of Urate Synthesis.- A. Introduction.- B. Inhibition of Xanthine Oxidase In Vitro.- C. Inhibition of Xanthine Oxidase In Vivo.- I. Exogenous Purines.- II. Inhibition of Uric Acid Production.- III. Oxypurines.- D. Pharmacokinetics and Clearance.- E. Metabolism.- I. Plasma and Urinary Metabolites.- II. Tissue Metabolites—Nucleotides.- F. Effects on Purine Biosynthesis.- G. Effects on Pyrimidine Biosynthesis.- H. Other Pharmacological Effects.- I. Iron Metabolism.- II. Protection from Ischemia.- III. Tryptophan Pyrrolase Inhibition.- IV. Drug Interactions.- V. Reduction of Urinary Calculi.- J. Toxicology.- K. Other Xanthine Oxidase Inhibitors.- I. Thiopurinol.- II. Other.- References.- 22 Enzymatic Uricolysis and Its Use in Therapy.- A. Introduction.- B. Properties of Urate Oxidase.- C. Pharmacologic Action of Urate Oxidase.- D. Therapeutic Trials of Enzymatic Uricolysis.- I. Urate Oxidase in Primary Hyperuricemia.- 1. Primary Asymptomatic Hyperuricemia.- 2. Hyperuricemia with Gout.- 3. Lesch-Nyhan Syndrome.- II. Secondary Hyperuricemia.- 1. In Renal Impairment.- 2. In Hemopathies.- 3. In Obesity.- III. Ophthalmology.- E. Tolerance.- I. Clinical Tolerance.- II. Immunologic Reactions.- F. The Use of Uricolytic Therapy: Limits, Indicators, Methods.- References.- 23 Pharmacology of Drugs Used in Treatment of Acute Gout.- A. Introduction.- B. Colchicine.- I. Brief History.- II. Structure and Structure/Function Relationships.- III. Metabolism.- IV. Mechanism of Action.- V. Clinical Use.- VI. Toxicology.- C. Phenylbutazone and Oxyphenbutazone.- I. Structure and Function.- II. Metabolism.- III. Clinical Use.- D. Indomethacin.- I. Structure.- II. Metabolism.- III. Mechanism of Action.- IV. Clinical Use and Toxicity.- E. Naproxen.- I. Chemical Structure.- II. Metabolism.- III. Mechanism of Action.- IV. Clinical Use.- F. Fenoprofen.- I. Chemical Structure.- II. Metabolism.- III. Mechanism of Action.- IV. Clinical Use.- References.- Author Index.